BBA - Bioenergetics 1860 (2019) 69–77

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BBA - Bioenergetics

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Review Regulated termination T ⁎ ⁎⁎ Daili Jia, Nikolay Manavskib, Jörg Meurerc, Lixin Zhanga,d, , Wei Chia, a Photosynthesis Research Center, Key Laboratory of Photobiology, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China b Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Moleculaire des Plantes, 12 rue du General Zimmer, 67084 Strasbourg, France c Molecular Biology, Faculty of Biology, Ludwig-Maximilians-University Munich, D-82152 Planegg-Martinsried, Germany d University of Chinese Academy of Sciences, Beijing 100049, China

ARTICLE INFO ABSTRACT

Keywords: Transcription termination by the RNA polymerase (RNAP) is a fundamental step of expression that involves Transcription termination the release of the nascent transcript and dissociation of the RNAP from the DNA template. However, the Chloroplast functional importance of termination extends beyond the mere definition of the gene borders. Transcription originate from and possess their own gene expression system. have a unique hybrid transcription system consisting of two different types of RNAPs of dissimilar phylogenetic origin together with MTERF several additional nuclear encoded components. Although the basic components involved in chloroplast tran- scription have been identified, little attention has been paid to the chloroplast transcription termination. Recent identification and functional characterization of novel factors in regulating transcription termination in Arabidopsis chloroplasts via genetic and biochemical approaches have provided insights into the mechanisms and significance of transcription termination in chloroplast gene expression. This review provides an overview of the current knowledge of the transcription termination in chloroplasts.

1. Introduction type nucleus-encoded RNA polymerase (NEP) and a prokaryotic type, plastid-encoded RNA polymerase (PEP) [9]. The PEP complex Viridiplantae possess two endosymbiotic , chloroplasts comprises four core subunits α, β, β′, and β″, which display high si- and mitochondria, in contrast to metazoa and fungi harboring only the milarities to counterparts in cyanobacteria. Beside the “eubacterial” latter. These organelles originated from cyanobacteria and alpha-pro- subunits, a number of additional nucleus-encoded of eu- teobacteria, respectively [1,2]. Although both organelles contain their karyotic origin involved in the chloroplast transcription have been own , most endosymbiotic have been transferred to the identified in the PEP complex, the plastid TRANSCRIPTIONALLY AC- nucleus or got lost over the course of - co-evolution TIVE (TAC) or the chloroplast via proteomic [3,4]. This has resulted in highly reduced organellar genomes that re- approaches [10–15]. The genetic data have shown that many of those tained only a small number of the original genes. Most of the organellar play important roles in the accumulation of PEP-depended mRNAs proteins are encoded by nuclear genomes, synthesized in the [15–17] and tRNAs [18]. It is assumed that they might provide addi- and subsequently imported into the organelles. Thus, the proper ex- tional regulatory functions that adapt chloroplast transcription in re- pression of genes requires the tight coordination between the organellar sponse to environmental signals and developmental cues, however, the and nuclear genomes [5–7]. molecular mechanisms still remain largely unknown. Chloroplast gene expression is rather complex. It combines both Termination is the last important step of transcriptional processes eubacterial and eukaryotic features derived from the cyanobacteria [19]. The role of transcription termination is not restricted to the re- ancestor or the host [6]. However, many features especially of the lease of the RNAP from the DNA template. The growing evidence in- organellar gene expression system also evolved de novo [8]. One ex- dicates that it is also important to avoid interference with expression of ample is the chloroplast transcription machinery. The transcription of downstream genes, to prevent formation of antisense and to en- chloroplast genes depends on two RNA polymerases (RNAPs): a phage- sure a pool of RNAPs available for reinitiation or new transcription

Abbreviations: RNAP, RNA polymerase; NEP, nucleus-encoded plastid RNA polymerase; PEP, plastid-encoded RNA polymerase; rut, Rho using termination; RNE, RNase E ⁎ Correspondence to: L. Zhang, University of Chinese Academy of Sciences, Beijing 100049, China. ⁎⁎ Correspondence to: W. Chi, Photosynthesis Research Center, Institute of Botany, Chinese Academy of Sciences, Nanxincun 20, Xiangshan, Beijing 100093, China. E-mail addresses: [email protected] (L. Zhang), [email protected] (W. Chi). https://doi.org/10.1016/j.bbabio.2018.11.011 Received 8 March 2018; Received in revised form 15 October 2018; Accepted 7 November 2018 Available online 08 November 2018 0005-2728/ © 2018 Elsevier B.V. All rights reserved. D. Ji et al. BBA - Bioenergetics 1860 (2019) 69–77

[20–22]. Termination mechanisms vary considerably in different or- resulted from transcription termination. The other half of the atpB 3′ ganisms, ranging from relatively simple to exceptionally complex pro- termini were produced by posttranscriptional processing events: in the cesses. In such as , there are at least two con- first step the long atpB precursor transcript is endonucleolytically served mechanisms of transcription termination: Rho-dependent cleaved and then further processed by 3′-5′ exonucleolytic digestion to termination and intrinsic termination (dissociation of the transcription produce the mature transcript [45,46]. In addition, when the native 3′ complexes is accomplished without the assistance of Rho factors) end of petD was replaced by a variety of 3′ ends from other chloroplast [23–25]. In yeast and mammal cells, three different strategies for genes in Chlamydomonas, none of the 3′ ends in either sense or antisense transcription termination have been developed depending on distinct orientation prevented read-through, indicating that the 3′ end se- RNAPs [26]: termination by RNAP II is coupled with the processing of quences of chloroplast genes are not efficient transcription terminators the pre-mRNA [27–29], RNAP III termination is an autonomous process [47]. Therefore, it has been proposed that most of the RNA stem loop occurring at T-rich sequences located at the 3′-end of the genes [30,31], structures formed at the 3′ ends of mature RNAs in Chlamydomonas and RNAP I relies on a specific composed of an oligo-dT chloroplasts might not be related to transcription termination. stretch and associated factors [32,33]. Interestingly, it was found that two tRNA genes, trnH1 and trnS, can Intriguing issues regarding the chloroplast transcription system are efficiently terminate transcription in a spinach in vitro transcription the mechanisms and significance of transcription termination. Due to system [43,48]. Furthermore, tRNA genes are often found downstream the cyanobacterial origin, one might expect that the termination ma- of several transcription units in the chloroplast genome of (e.g., chinery in chloroplasts is similar to that of bacteria. However, no atpBE, rrnV1; psaAB; tmfM; atpHFA, tmS3; psbA, tmH1)[49]. Thus, it homologs of known bacterial proteins involved in transcription termi- seems as if different vascular plant chloroplast tRNA genes might have a nation have been identified in chloroplasts so far. In addition, it is potential role in both termination and punctuation [50], which was generally accepted that it is the RNA maturation rather than the tran- originally established in vertebrate mitochondrial. The vertebrates scription termination that creates defined 3′ termini [34,35]. Thus, the mitochondrial genome is transcribed symmetrically as polycistronic degree to which the transcription termination affects chloroplast gene precursors spanning the entire heavy and light strands [51], however, expression remains an open question. For a long time, the termination the 22 tRNAs interspersed throughout the mitochondrial genome serve of transcription in chloroplasts has received relatively little attention as punctuation marks that are recognized and cleaved at 5′ and 3′ ends until two publications appeared that provided insights into the reg- by the mitochondrial nucleases to be process later on into mature ulation of chloroplast transcription termination in Arabidopsis [36,37]. species [50,52]. However, this concept does not hold true for Chlamy- In this short review, we will summarize the progress that has been made domonas chloroplasts [45,46]. in terms of the mechanism of chloroplast transcription termination, Despite these considerations, it is generally thought that the 3′ in- focusing especially on the functions of RHON1 and mTERF6, and pro- verted repeat sequences of chloroplast genes do not represent efficient vide perspectives in this area. Although some knowledge of chloroplast termination signals [45–47 ]. However, their role in termination activity transcription termination arises from that of bacteria, mechanisms of could not be ruled out completely based on current evidences in spi- transcription termination in bacteria will not be presented in details nach or Chlamydomonas, showing that for some genes (e.g. petD and due to the space limitation. Those, who wish to obtain further details atpB) the inverted repeats can still terminate transcription with a con- about transcription termination in bacteria, are referred to the review siderable efficiency [43,46]. In addition, chloroplast RNAPs can effi- articles of Peters et al. [25] and Mitra et al. [38]. ciently recognize bacterial threonine, histidine, and T7 early Rho-in- dependent terminators [53–56], suggesting that a specific unknown 2. Transcription termination in chloroplasts RNA structure and/or sequence that might not be related to inverted repeats can indeed terminate the transcription of chloroplast RNAPs. 2.1. Does the 3′ stem-loop structure present in some chloroplast genes The termination activity at 3′ ends of petD and atpB might result from function as transcription terminator? this unknown RNA structure and/or sequence. In addition, termination of transcription by spinach chloroplast RNAP was also modulated by The intrinsic transcription termination in bacteria depends on a downstream DNA sequences in a sequence-specific manner [57]. In this hairpin structure in the nascent RNA which leads to the release of the context, the structure/sequence-dependent termination still holds true transcript and the RNAP from the DNA template without the assistance in chloroplasts of vascular plants but might be more complicated than of additional factors [25,39]. DNA sequence analyses have revealed expected. that inverted repeat sequences are present in the 3′ end of many A canonical intrinsic terminator of Escherichia coli is an RNA signal chloroplast genes, including rbcL, petD, psbA, psbC, and rpoA [40,41]. composed of a GC-rich RNA hairpin followed by a run of U residues. The inverted repeat sequences can fold into stem-loop structures similar Termination occurs in two steps: RNAP pausing within the U track, to the intrinsic terminators in E. coli. Thus, it seems reasonable to followed by RNA release [39]. However, most of the hairpin structures speculate that the inverted repeat sequences in plastid DNA might formed at the 3′ UTRs of chloroplast mRNAs do not fit with this feature. function as intrinsic transcription terminators for chloroplast RNAP In fact, the role of the termination hairpins appears to be indirect as it [42]. can be replaced by oligonucleotides that pair to the nascent RNA to Whether the inverted repeat sequences of 3′ ends of chloroplast mimic the hairpins [58,59], suggesting the structural flexibility of 3′ genes can actually act as transcription terminators was firstly addressed UTR is involved in transcription termination. The intrinsic terminator by Stern and Gruissem [43] by means of a homologous in vitro tran- signals can only be frequently identified in E. coli but many other scription system from spinaches. They found that of inverted repeat bacterial and archaeal genomes lack such intrinsic terminator signals sequences in the 3′ end of psbA, rbcL, petD, and rpoA, only the petD [60], implying the existence of a different type of signal or dependence inverted repeat was partially effective as a transcription terminator in on a in these species. These findings further support this in vitro assay. Based on this study, it was proposed that the role of the assumption that structure/sequence correlations not related to chloroplast inverted repeats is not to terminate transcription but to hairpin structures accomplish chloroplast transcription termination. stabilize transcripts by either preventing 3′-5′ exonucleolytic activity It has been suggested that PEP predominantly mediates the tran- and/or by serving as a platform for RNA-binding proteins that protect scription of photosynthesis-related genes while NEP rather mediates the the transcripts from degradation [44]. transcription of the house keeping genes [61–64]. Nevertheless, this This notion was further supported by in vivo evidence from division of labor between PEP and NEP is also a challenge because NEP Chlamydomonas reinhardtii chloroplasts [45–47]. It was found that less is in fact able to transcribe the complete plastid genome [65]. In ad- than 50% of 3′ ends of atpB transcripts in Chlamydomonas chloroplasts dition, most plastid genes (including genes coding for photosynthesis

70 D. Ji et al. BBA - Bioenergetics 1860 (2019) 69–77 proteins) have both PEP and NEP promoters [63,66–69]. So far, almost all of the studies for the chloroplast transcription termination have focused on PEP-dependent genes whereas mechanisms of NEP-depen- dent genes remain elusive. The NEP is similar to single-subunit phage RNAPs which are found to terminate at both class I and class II termi- nation signals. The former is similar to intrinsic termination signals of bacterial RNAP, however, the latter consists of a conserved sequence, HATCTGTT (H designating A, C, or T) [70–72]. No class II-like termi- nation signal has been identified in chloroplast transcripts yet and it is still unknown whether the NEP relies on the class I or class II termi- nation signals. If it is the latter, the NEP and PEP seem to employ dis- tinct intrinsic mechanisms to terminate transcription in chloroplasts. Thus, it is of interest to address whether the distinct termination me- chanisms of NEP and PEP relate to the division of labor between PEP and NEP if this division really exists in planta [67–69].

2.2. Is there a Rho-dependent termination in chloroplasts?

The Rho-dependent termination is the major way to terminate the transcription in eubacteria and the transcription termination of a large fraction of genes relies on this mechanism in E. coli (reviewed by [73], the process is depicted in Fig. 1). The Rho factor is a ring-shaped, homohexameric that utilizes its RNA-dependent ATPase activity to translocate along the mRNA and to eventually dislodge the RNAP [23,38]. In E. coli, Rho is a 419-amino acid protein containing several domains. The N-terminal domain of Rho contains the primary RNA- binding site. Its C-terminal domain (CTD) contains an ATP-binding and hydrolysis signature motif, called the P-loop, which shows significant to F1 ATPases [74–76]. No homologs of the Rho factor are found in chloroplasts of vascular plants or Chlamydomonas, suggesting that the Rho-dependent termina- tion might not exist in chloroplasts. However, the BLAST analysis of the Arabidopsis genome showed that several chloroplast proteins contain RNA-binding domains, which are similar to primary RNA-binding do- mains located at the N-terminus of Rho factors (Table 1). These proteins were referred to as RHON proteins. Besides its role in supporting RNase E (RNE) activity [77], the study of Chi et al. [36] showed that the chloroplast RHON1 protein is also involved in the transcription termi- nation of rbcL. RHON1 was originally identified in a screen for interaction partners of the endonuclease RNE. It was shown that RHON1 is involved in RNE- mediated plastid RNA processing by conferring sequence specificity to the RNE through its RNA-binding activity [77]. Similar to rne mutants, several plastid RNA precursors accumulated in rhon1 mutant, one of which is a large RNA precursor spanning the rbcL, accD, psaI, ycf4, cemA, and petA genes [77]. A PEP (PrbcL-179) is responsible for the generation of monocistronic rbcL [78] whereas two NEP pro- moters (PaccD-172, 252) have been found to drive transcription of the Fig. 1. Model of Rho-dependent termination. Arabidopsis accD gene [79]. In this context, the transcription of rbcL and (a) Hexameric Rho loaded onto the RNA transcript at rut sites at the time of accD seem to be independent. However, a large polycistronic precursor termination. Cofactors of Rho (NusG, NusA, H-NS, YaeO, Psu, Hfq) are in- transcript of accD-psaI-ycf4-cemA-petA was also reported [80]. The RNA dicated; (b) Rho catches up with the RNAP; (c) rut RNA remains bound to the gel blot analyses showed that levels of both the precursor and mature Rho-NTD during translocation, forming a loop between the primary and sec- forms of accD, psaI, ycf4, cemA, and petA mRNAs were increased, ondary RNA-binding sites; (d) Rho contacts the elongation complex (EC). The whereas levels of monocistronic rbcL remained unchanged in rhon1.If presence of NusG and ATP accelerates the conformational change of RNAP; (e) RHON1 is involved in the cleavage of this precursor, the transcription dissociation of the EC. rates of accD, psaI, ycf4, cemA, and petA should not be changed. How- ever, a run-on assay showed that the transcription rates of accD, psaI, specifically bind to the mRNA as well as to single-stranded DNA of the ycf4, cemA, and petA were increased in rhon1 plants but the transcrip- rbcL 3′ UTR. Secondly, RHON1 displays ATPase activity depending on ff tion rates of rbcL were not a ected. Considering this, the increase of its RNA-binding ability. These two features are similar to those of accD, psaI, ycf4, cemA, and petA transcription rate might result from the bacterial Rho factors. More direct evidence came from an in vitro reading-through of rbcL [36]. Therefore, this genetic evidence pointed transcription termination assay displaying that RHON1 could actually to the possibility that RHON1 is involved in rbcL transcription termi- terminate transcription of rbcL depending on ATPase activity [36]. nation rather than in the post-transcriptional processing of the rbcL- Thus, RHON1 seems to terminate rbcL transcription in a similar way to accD-psaI-ycf4-cemA-petA precursor [36]. that of the Rho factor in Escherichia coli. However, the mechanism of Further biochemical analyses showed that RHON1 might be able to termination between chloroplast RHON1 and eubacterial Rho factors terminate rbcL transcription similar to Rho factors. Firstly, RHON1 can

71 D. Ji et al. BBA - Bioenergetics 1860 (2019) 69–77

Table 1 Homologs of the Rho protein and cofactors in Arabidopsis.

Group Name Gene Location Function References

Group I: The Rho Cluster RHON1 AT1G06190 C Rho termination factor [36] – AT4G18740 M/C/Y Rho termination factor – – AT2G41550 N/O Rho termination factor – Group II: The NusG Cluster PTAC13 AT3G09210 C/M Plastid transcriptionally active 13 [11] Spt5 AT2G34210 N/O Putative transcription elongation factor SPT5 [92] KTF1 AT5G04290 N SPT5-LIKE, transcription regulation [93,94] GTA2 AT4G08350 N SPT5-LIKE, transcription regulation [92] Group III: The NusA Cluster RAD51 AT5G20850 N/M DNA repair (Rad51) family protein; unwinds duplex DNA by DNA-dependent ATPase activity [95,96] DMC1 AT3G22880 N DNA repair/DNA metabolic process, DNA-dependent ATPase activity. [97–99]

Homologs of the Rho protein and Rho cofactors identified in the Arabidopsis genome. The subcellular localization was predicted by TargetP. Bold lettering indicates the cellular compartment to which the gene products are targeted. C, chloroplast; M, mitochondria; N, nucleus; O, others; Y, cytosol. might be different. The mRNA region bound by RHON1 (between 88 [105,107], suggesting the regulatory function of antisense RNAs in and 133 nucleotides downstream of the rbcL termination codon) does chloroplast gene expression. Given that one consequence of inefficient not show any similarity to rut (Rho using termination) signal sequences transcriptional termination is the production of antisense RNAs [110], which is recognized by Rho factors [38]. The RHON1-binding sequence one might argue that transcriptional termination affects chloroplast contains only few C residues compared to that of Rho. In addition, the gene output by modulating the generation of antisense RNAs. However, ATPase domain of RHON1 belongs to P-type ATPases rather than to the this possibility has not been addressed experimentally yet. The study of F-type in Rho. Therefore, it stands to reason that the mechanism of Chi et al. [36] showed that the inefficient termination of rbcL actually action of RHON1 is not identical to that of Rho factors. affects the expression of the downstream accD gene presumably by a The Rho-dependent mechanism seems not to be restricted to eu- transcription interference mechanism [36]. bacteria and chloroplasts of vascular plants, as similar ATP-driven Transcriptional interference is defined as the suppressive influence termination machineries have also been discovered in eukaryotic cells of one transcriptional process on a second downstream located tran- [81]. For instance, Sen1p is the key enzyme of the termination reaction scriptional process due to the read-through [111]. Transcriptional in- in yeast cells. Like the bacterial termination factor Rho, Sen1p re- terference can occur between convergent (face-to-face), tandem (co- cognizes the nascent RNA and hydrolyzes ATP to dissociate the elon- directional), or overlapping arrangements of promoters, where the as- gation complex [82,83]. sociation and elongation of RNAPs from one promoter disrupts RNAPs The function of Rho requires several cofactors in bacterial systems, and/or transcription factors at a second promoter [112–115]. It is po- including NusG [84,85], NusA [86,87], H-NS [88], YaeO [89], Psu tentially widespread in and has been addressed in yeast and [90], and the RNA chaperone Hfq [91]. Interestingly, homologs of bacterial cells [114,115]. However, whether or not it also exists in NusG and NusA are also found in vascular plants (Table 1)[92–99]. chloroplasts still remains an open question. There are five NusG homologs in Arabidopsis. One is called pTAC13 In the rhon1 mutant, an intriguing finding is the fact that the tran- [11]. The function of pTAC13 still remains unknown and it is of interest scription initiation of accD is altered significantly (Fig. 2). In WT plants, to address the question whether its function is related to chloroplast there are two NEP-dependent transcription start sites for accD:PaccD- transcription termination. In E. coli, Rho acts on a naked nascent 252 and PaccD-172 [79]. However, in rhon1 multiple transcription in- transcript that is not engaged in or bound to RNA-binding itiation sites of accD scattered all over the rbcL-accD intergenic region proteins. However, RHON1 exists as a large RNA-protein complex in were identified. Some transcription initiation sites were even mapped vivo and directly binds to RNE [77]. This difference between RHON1 within the 5′-end of the accD coding region. In addition, these transcript and Rho factors suggests a possible link between chloroplast tran- initiation sites disappeared when rhon1 seedlings were treated with scription termination and RNA processing. spectinomycin, suggesting that they depend on upstream rbcL tran- Termination of rbcL transcription was originally inferred from the scription [36]. It is likely that this is a consequence of inefficient transformation of the plastid genome of Nicotiana tabacum [100–102]. transcription termination of rbcL. Thus, one of the functions of RHON1 When plastid vectors were targeted to the rbcL-accD intergenic region of in efficient termination of transcription may be to avoid aberrant the tobacco plastid genome [103], rbcL read-through transcripts were transcription initiation in the rbcL-accD intergenic region. detectable [101–104]. However, when the insertion site was moved If the aberrant transcription initiation in the rbcL-accD intergenic 170 nucleotides further downstream of rbcL, the rbcL read-through was region can be regarded as the consequence of transcription interference eliminated [103]. Therefore, the presence of a termination or proces- and how this transcription interference occurs is still an open question. sing site in the intergenic region of rbcL and accD has been proposed. A previous study has shown that chloroplast transcription initiation However, whether a termination or processing site has been disrupted sites in vascular plants are not very stringent [79,116]. The elongating in the resulted tobacco transformants has not been addressed further. In RNAP complex across the termination site of rbcL might interfere with the context of RHON1 function, it is very likely that there is a termi- the transcription initiation complex of the accD transcriptional unit and nation site between rbcL and accD. However, this does not exclude the reduce the transcription accuracy. Alternatively, PEP might not be re- presence of a possible processing site as well. leased from the template due to the lack of RHON1; it might slide on the template and finally reinitiate transcription nonspecifically at different positions in the rbcL-accD intergenic region. Nevertheless, as mentioned 2.3. Significance of RHON1-dependent transcription termination above, accD is exclusively transcribed by NEP while rbcL is mainly transcribed by PEP. These two distinct RNAPs recognize different pro- The antisense RNAs play important roles in posttranscriptional moters via different mechanisms but the competition between both regulation and numbers of antisense RNAs have been detected in enzymes has not been described yet. In addition, unspecific initiation by chloroplasts [66,105–109]. Some antisense RNAs of chloroplasts might PEP can occur only at a nick in the DNA template, one of the reasons inhibit the translation of sense RNAs encoded on the opposite strand why sonicated DNA is used for unspecific transcription activity assays [108,109] or protect unstable transcripts from 3′ → 5′ exonuclease ac- of PEP preparations [117]. It is unlikely that such DNA template defects tivity by the formation of double-stranded RNA/RNA hybrids

72 D. Ji et al. BBA - Bioenergetics 1860 (2019) 69–77

Fig. 2. Model of RHON1 action in rbcL transcription termination. Left: RHON1 binds to the elements adjacent to the stem-loop structure of the rbcL 3′ UTR via its RNA binding domain (RD). After binding to its target, RHON1 catalyzes the dissociation of rbcL mRNA from genomic DNA and RNAP via its ATPase domain (AD). Right: When RHON1 is absent, read-through products of rbcL are produced. In addition, aberrant transcription initiation of accD occurs, which might result from the transcription interference in the rbcL-accD intergenic region. occur in rhon1 mutant. Considering these conflicts, it is an enormous MTERF proteins: MTERF1-MTERF4. Human mTERF1 was the first challenge to dissect the mechanism of the transcription interference identified mTERF factor that promotes transcription termination in between NEP and PEP in this transcription unit, if it really exists. In mitochondria and thus the whole family was named accordingly yeast cells, the transcription interference usually reduces the promoter [128–130]. MTERF1 is a DNA-binding protein of 39 kDa that interacts activity of downstream genes [114] and such aberrant transcription with a 28 bp region within the tRNALeu gene, located immediately initiation has never been reported for other chloroplast transcription downstream of the rRNA genes in the mitochondrial genome [131]. The units but might be worth studying in the future. association of MTERF1 with its target site has been reconstituted in a The interplay between rbcL and accD expression mediated by pure recombinant in vitro system [132], suggesting that MTERF1 might RHON1 also contributes to the developmental profile of accD mRNA function in H-strand transcription. However, further studies showed accumulation. The expression of plastid genes generally varies in re- that MTERF1 only partially terminates H-strand transcription, whereas sponse to developmental signals depending on the RNAP and promoter transcription in the opposite direction (L-strand transcription) is almost usage [70,118–121]. As preferential NEP-dependent gene, accD tran- completely blocked [133]. The in vivo study in mTERF1 knockout mice script accumulation is subjected to a dynamic pattern during chlor- showed that the main function of MTERF1 is indeed to prevent L-strand oplast development [67,122]. However, the inefficient transcription transcripts from proceeding around the mtDNA circle and causing termination of rbcL impaired the expression profile of accD, resulting in transcription interference at the L-strand promoter from which they the constitutive transcription of accD during chloroplast development originated [133]. Nevertheless, the human MTERF1 protein might [123]. In addition, the accumulation of accD transcripts accordingly possess multiple functions. It is also supposed to function as an activator resulted in an increase in AccD protein and fatty-acid contents, sug- of mitochondrial rRNA transcription and modulator of mtDNA re- gesting that inefficient rbcL transcription termination might lead to the plication [134,135]. physiological changes in the chloroplast [123]. The have Plant genomes harbor a considerably larger number of MTERFs than been reported to possess crucial biosynthetic functions, one of which is genomes. Arabidopsis and rice contain at least 35 and 48 MTERF the biosynthesis of long-chain fatty-acid in developing [124]. proteins, respectively [126,136], and even more have been proposed Thus it is of interest to study the effects of such interplay between rbcL for other plant species. Nonetheless, only nine MTERFs have been and accD expression on the biogenesis and function. characterized in land plants and Chlamydomonas. Among them, MOC1 [137], SHOT1 [138] and MTERF15 [139] are located in mitochondria; 2.4. The possible role of mTERF in chloroplast transcription termination BSM/RUG2 [140,141] and MTERF6 [37] are located in both chlor- oplast and mitochondria, while MDA1, MTERF9 [142,143], SOLDT10 The mTERF protein family is proposed to be the result of the ex- [144], and zmMTERF4 [145] are exclusively located in chloroplast. The pansion and functional diversification of existing gene families. wide distribution of MTERF proteins in organelles along with their Proteins of this family contain variable repeats of a 30-amino-acid proposed RNA/DNA-binding properties suggests that they might have a motif, the so-called MTERF motif [116,125–127]. Vertebrates have four role in organellar gene expression. Actually, at least three members of

73 D. Ji et al. BBA - Bioenergetics 1860 (2019) 69–77 plant MTERFs (BSM/RUG2, MTERF15, zmMTERF4) are found to its location on chloroplast genome among different species is still an function in organellar intron splicing [139–141,145]. open question. Further studies on the chloroplast transcription termi- MOC1 is the first characterized mTERF protein that terminates nation in an evolutionary context will be necessary to shed light on mitochondrial DNA transcription in Chlamydomonas [137]. MOC1 binds these processes. specifically to the mitochondrial rRNA-coding module S3. However, One striking feature of chloroplasts is the existence of penta- levels of rRNA-coding modules were only mildly affected, indicating tricopeptide repeat (PPR) proteins which constitute one of the largest that the read-through does not occur at the S3 binding site in moc1 protein families in land plants [148]. Some PPR proteins have been mutants. Instead, as in mterf1 knock-out mice, the level of certain an- proposed to be protective factors for 3′-ends of chloroplast RNAs [148]. tisense RNA species was increased in moc1 mutant, suggesting that If transcription and RNA processing are inherently linked in chlor- MOC1 acts as a transcription terminator of antisense RNA. The mTERF- oplasts, the possible direct (or indirect) role of PPR proteins in tran- mediated transcription termination seems to be an evolutionary-con- scription termination could not be overlooked. Preliminary experiments served mechanism occurring in phototrophic and metazoa. have identified a leucine-rich pentatricopeptide repeat-containing The study of Romani et al. [37] raises the possible function of protein that appears to bind at the mouse HSP distal termination region Arabidopsis MTERF6 (AtMTERF6) in the transcription termination of [149], suggesting the possible role of PPR proteins in mitochondrial chloroplast tRNAIle. AtMTERF6 is localized in both chloroplast and transcription termination. The further elucidation of the role of PPR mitochondria [136]. In the leaky mterf6-1 mutant, the maturation of proteins in chloroplast transcription termination will provide insight chloroplast ribosomal RNAs (rRNAs) is perturbed in mterf6-1 mutants. into this area. In vitro and in vivo analyses proved that mTERF6 can bind to the chloroplast trnI.2 [tRNAIle(GAU)] located downstream of the rrn16 in Transparency document the rrn gene cluster. This binding site of MTERF6 is similar to that of mTERF1 in their relative positions in the organelle genomes [133]. The Transparency document associated with this article can be Recombinant AtMTERF6 can bind to its chloroplast DNA target site and found, in online version. terminates transcription in vitro. In addition, an intact mTERF6 target site is necessary for correct transcription termination and mutations in Acknowledgements this target site resulted in abnormal transcription termination. Con- sidering the sequence similarity between human MTERF1 and AtM- This work was supported by the Ministry of Agriculture of the TERF6, it seems that mTERF6 protein is able to promote transcription People's Republic of China [grant number: 2016ZX08009003-005 to termination in vitro [37]. In atmterf6 mutants, the levels of downstream W.C.], the Strategic Priority Research Program of CAS [grant number: trnA.1 transcripts were increased; however, whether this resulted from XDB17030100 to W.C.], the Major State Basic Research Development the read-through of trnI.2 and the impact of AtMTERF6 on the tran- Program [Grant number: 2015CB150100 to L.Z.] and the Deutsche scription on the opposite strand of chloroplast DNA have not been in- Forschungsgemeinschaft [TRR 175, project A03 to J.M.]. vestigated yet. Whether AtMTERF6 functions in the transcription ter- mination of antisense RNA like MOC1 still awaits further investigations. References

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